U.S. patent application number 12/165202 was filed with the patent office on 2008-12-04 for cooling compounds.
This patent application is currently assigned to Givaudan SA. Invention is credited to Stefan Michael Furrer, Christophe C. Galopin, Pablo Victor Krawec, Jay Patrick Slack, Lori W. Tigani.
Application Number | 20080300314 12/165202 |
Document ID | / |
Family ID | 40089007 |
Filed Date | 2008-12-04 |
United States Patent
Application |
20080300314 |
Kind Code |
A1 |
Galopin; Christophe C. ; et
al. |
December 4, 2008 |
Cooling Compounds
Abstract
Compounds of the formula I give a cooling sensation to the mouth
and skin: ##STR00001## In Formula I, m is 0 or 1; X is
--(CH.sub.2).sub.n--R, where n is 0 or 1 and R is selected from
--OR'. --COOH, --COOR'', --SO.sub.2NH.sub.2, --CHO, --COR''', and
--CN, R' being selected from H and C.sub.1-C.sub.3 straight- and
branched-chain alkyl. R'' from C.sub.1-C.sub.4 straight- and
branched-chain alkyl and R''' from C.sub.1-C.sub.3 straight- and
branched-chain alkyl: Y is selected from H, --COOH and --OR''',
where R''' has the significance previously referred to; and Z is H;
with the provisos that (iii) When Y is H and X is any of the
abovementioned significances, except --CN and --COOH, X is in the
4-position; (iv) when Y has a significance other than H, it is in
the 5-position when X is in the 2-position and in the 6-position
when X is in the 3-position. The compounds give a cooling sensation
that can be more powerful than the best current commercial
materials.
Inventors: |
Galopin; Christophe C.;
(Chesterfield, VA) ; Krawec; Pablo Victor;
(Cincinnati, OH) ; Slack; Jay Patrick; (Loveland,
OH) ; Tigani; Lori W.; (Salisbury, MD) ;
Furrer; Stefan Michael; (Cincinnati, OH) |
Correspondence
Address: |
CURATOLO SIDOTI CO., LPA
24500 CENTER RIDGE ROAD, SUITE 280
CLEVELAND
OH
44145
US
|
Assignee: |
Givaudan SA
Vernier
CH
|
Family ID: |
40089007 |
Appl. No.: |
12/165202 |
Filed: |
June 30, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11437294 |
May 19, 2006 |
7414152 |
|
|
12165202 |
|
|
|
|
PCT/CH2004/000646 |
Oct 28, 2004 |
|
|
|
11437294 |
|
|
|
|
60523977 |
Nov 21, 2003 |
|
|
|
Current U.S.
Class: |
514/621 ;
514/622; 558/410; 564/161; 564/170 |
Current CPC
Class: |
A61K 2800/244 20130101;
A61K 8/42 20130101; C07C 255/44 20130101; C07C 255/60 20130101;
C07C 311/46 20130101; C07C 2601/14 20170501; C07C 233/60 20130101;
A61Q 19/00 20130101; C07C 233/61 20130101; C07C 233/63 20130101;
A61Q 11/00 20130101 |
Class at
Publication: |
514/621 ;
564/170; 564/161; 514/622; 558/410 |
International
Class: |
A61K 8/42 20060101
A61K008/42; C07C 255/20 20060101 C07C255/20; C07C 235/32 20060101
C07C235/32; A61Q 19/00 20060101 A61Q019/00 |
Claims
1. A compound of formula I ##STR00024## wherein m is 0 or 1; X is
--(CH.sub.2).sub.n--R. Where n is 0 or 1 and R is selected from the
group consisting of --OR', --COOH, --COOR'', --SO.sub.2NH.sub.2,
--CHO, --COR''', and --CN, R'' being selected from the group
consisting of H and C.sub.1-C.sub.3 straight- and branched-chain
alkyl). R''' being selected from the croup consisting of
C.sub.1-C.sub.4 straight- and branched-chain alkyl and R''' being
selected from the group consisting of C.sub.1-C.sub.3 straight- and
branched-chain alkyl; and Y is selected from the group consisting
of H, --COOH and --OR''', where R''' has the significance
previously referred to; and Z is H; with the provisos that (i) when
Y is H, X is not --OH, --CN, --OMe Or --COOH in the 4-position and
not --OH in the 2-position; (ii) when Y has a significance other
than H, Y is in the 5-position when X is in the 2-position and in
the 6-position when X is in the 3-position; (iii) the groups in the
3- and 4-positions are not both OMe, (iv) the groups in the 4- and
5-positions are not both OMe, (v) the groups in 3- and 5-positions
are not OMe if the group in the 4-position is OH, and; (vi) the
groups in the 3- and 5-positions are not OH if the croup in the
4-position is methyl.
2. A compound according to claim 1, in which X is in the
4-position.
3. A compound according to claim 2, in which Y is selected from the
group consisting of H, OH, Me and OMe.
4. A compound according to claim 1, in which the
2-isopropyl-5-methylcyclohexane moiety has the stereochemical
configuration (1R, 2S, 5R).
5. A compound according to claim 4, in which (a) m=0 (b) X is in
either the 2- or the 4-position, and when in the 2-position is CN
and when in the 4-position is selected from the group consisting of
--COOH, --COOCH.sub.3, --COOCH.sub.2CH.sub.3, --CN and
--SO.sub.2NH.sub.2; and (c) Y is selected from --CH.sub.3 in the
2-position and --OCH.sub.3 in the 3-position.
6. A compound according to claim 1, in which. (i) when Y is H and X
is any of the significances of claim 1, except --CN and --COOH, X
is in the 4-position; (ii) when Y is a moiety other than H, Y is in
the 5-position when X is in the 2-position, and Y is in the
6-position when X is in the 3-position.
7. A compound according to claim 1, in which (a) m=0, (b) X is in
either the 2- or the 4-position, and when in the 2-position is CN
and when in the 4-position is selected from the group consisting of
--COOH, --COOCH.sub.3, --COOCH.sub.2CH.sub.3, --CN and
--SO.sub.2NH.sub.2; and (c) Y is selected from --CH.sub.3 in the
2-position and --OCH.sub.3 in the 3-position.
8. A compound according to claim 1 selected from the group
consisting of (1R, 2S, 5R)--N--
(4-isopropoxybenzyl)-2-isopropyl-5-methylcyclohexanecarboxamide;
(1R, 2S,
5R)-2-isopropyl-5-methyl-N-(4-propionylphenyl)-cyclohexanecarboxamide;
methyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-2-methoxybenzoate;
butyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; ethyl
3-((1R, 2R,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-4-propoxybenzoate;
ethyl 2-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-4-methoxybenzoate;
methyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-3-methylbenzoate;
tert-butyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; methyl
4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; ethyl
4-(1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamide)benzoate;
2-[(2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-benzoic acid
methyl ester; 2-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid; (1R,
2S,
5R)-N-(4-formylphenyl)-2-isopropyl-5-methylcyclo-hexanecarboxamide;
2-isopropyl-5-methyl-cyclohexanecarboxylic acid
(2,4-dimethoxy-phenyl)-amide;
2-isopropyl-5-methyl-cyclohexanecarboxylic acid
(2-hydroxy-4-methyl-phenyl)-amide; ethyl 2-((1R, 2S
,5R)-2-isopropyl-5-methylcyclohexanecarboxamido)benzoate; 4-((1R,
2S, 5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid;
4-(((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)methyl)benzoic
acid; (1R, 2S,
5R)-N-(4-cyanobenzyl)-2-isopropyl-5-methylcyclohexanecarboxamide- ;
2-hydroxy-5-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid; (1R,
2S,
5R)-2-isopropyl-5-methyl-N-(4-sulfamoylbenzyl)-cyclohexanecarboxamide;
4-(((1R, 2S,
5R)-2-isopropyl-5-methyl-cyclohexanecarboxamido)-methyl)benzoic
acid; ethyl 2-(4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)phenyl)acetate.
(1R, 2S,
5R)-N-(2-cyanophenyl)-2-isopropyl-5--methylcyclohexane-carboxamide;
and, (2S,
5R)-N-(3-cyanophenyl)-2-isopropyl-5-methylcyclohexane-carboxamide.
9. A method of providing a cooling effect to the mouth or skin by
applying thereto a product comprising a compound according to claim
1.
10. The method of claim 9 wherein said applying, comprises
inhalation.
11. The method of claim 9 wherein said applying comprises oral
ingestion.
12. A method according to claim 9 wherein tile compound is selected
from the group consisting of (1R, 2S,
5R)-N-(4-isopropoxybenzyl)-2-isopropyl-5-methylcyclohexanecarboxamide;
(1R, 2S,
5R)-2-isopropyl-5-methyl-N-(4-propionylphenyl)-cyclohexanecarbox-
amide; methyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-2-methoxybenzoate;
butyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; ethyl
3-((1R, 2R,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-4-propoxybenzoate;
ethyl 2-((1R, 2S, 5R)-2-isopropyl-5-
methylcyclohexane-carboxamido)-4-methoxybenzoate; methyl 4-((1R,
2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-3-methylbenzoate;
tert-butyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; methyl
4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; ethyl
4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate;
2-[(2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-benzoic acid
methyl ester; 2-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid; (1R,
2S,
5R)-N-(4-formylphenyl)-2-isopropyl-5-methylcyclo-hexanecarboxamide;
2-isopropyl-5-methyl-cyclohexanecarboxylic acid
(2-4-dimethoxy-phenyl)-amide;
2-isopropyl-5-methyl-cyclohexanecarboxylic acid
(2-hydroxy-4-methyl-phenyl)-amide; ethyl 2-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexanecarboxamido)benzoate; 4-((1R,
2S, 5R)-2-isopropyl)5-methylcyclohexane-carboxamido)benzoic acid;
4-(((1R, 2S, 5R)-2-
isopropyl-5-methylcyclohexane-carboxamido)methyl)benzoic acid; (1R,
2S,
5R)-N-(4-cyanobenzyl)-2-isopropyl-5-methylcyclohexanecarboxamide- ;
2-hydroxy-5-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid; (1R,
2S,
5R)-2-isopropyl-5-methyl-N-(4-sulfamoylbenzyl)-cyclohexanecarboxamide;
4-(((1R, 2)S,
5R)-2-isopropyl-5-methyl-cyclohexanecarboxamido)-methyl)benzoic
acid- ethyl 2-(4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)phenyl)acetate;
(1R, 2S,
5R)-N-(2-cyanophenyl)-2-isopropyl-5-methylcyclohexane-carboxamide;
and, (2S,
5R)-N-(3-cyanophenyl)-2-isopropyl-5-methylcyclohexane-carboxamide.
13. A product that is applied to the mouth or the skin comprising
an effective amount of a compound according to claim 1, wherein the
amount is effective to give a cooling sensation.
14. The product of claim 13 comprising at least one of tobacco
products, consumable products, oral care products, or cosmetic
products.
15. The product of claim 13 further comprising an additional
cooling compound.
16. The product of claim 15 wherein the additional cooling compound
comprises at least one of menthol, menthone, isopulegol, N-ethyl
p-menthanecarboxamide, N,2,3-trimethyl-2-isopropylbutanamide,
methyl lactate, menthone glycerine acetal, mono-menthyl succinate,
mono-menthyl glutarate, O-menthyl glycerine,
menthyl-N,N-dimethylsuccinamate, or 2-sec-butylcyclohexanone.
17. The product of claim 13 wherein the compound according to claim
1 is selected from the group consisting of (1R, 2S,
5R)-N-(4-isopropoxybenzyl)-2-isopropyl-5-methylcyclohexanecarboxamide;
(1R, 2S,
5R)-2-isopropyl-5-methyl-N-(4-propionylphenyl)-cyclohexanecarbox-
amide; methyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-2-methoxybenzoate
butyl-4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; ethyl
3-((1R, 2R,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-4-propoxybenzoate;
ethyl 2-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-4-methoxybenzoate:
methyl) 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)-3-methylbenzoate;
tert-butyl 4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; methyl
4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate; methyl
4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoate;
2-[(2-isopropyl-5-methyl-cyclohexanecarbonyl)-amino]-benzoic acid
methyl ester; 2-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid; (1R,
2S,
5R)-N-(4-formylphenyl)-2-isopropyl-5-methyl-cyclohexanecarboxylic
acid (2,4-dimethoxy-phenyl)-amide;
2-isopropyl-5-methyl-cyclohexanecarboxylic acid
(2-hydroxy-4-methyl-phenyl)-amide; ethyl 2-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexanecarboxamido)benzoate; 4-((1R,
2S, 5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid;
4-(((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)methyl)benzoic
acid-(1R, 2S,
5R)-N-(4-cyanobenzyl)-2-isopropyl-5-methylcyclohexanecarboxamide;
2-hydroxy-5-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)benzoic acid; (1R,
2S,
5R)-2-isopropyl-5-methyl)-N-(4-sulfamoylbenzyl)-cyclohexanecarboxamide;
4-(((1R, 2S,
5R)-2-isopropyl)-5-methyl-cyclohexanecarboxamido)-methyl)benzoic
acid; methyl 2-(4-((1R, 2S,
5R)-2-isopropyl-5-methylcyclohexane-carboxamido)phenyl)acetate;
(1R, 2S,
5R)-N-(2-cyanophenyl)-2-isopropyl-5-methylcyclohexane-carboxamide;
and, (2S,
5R)-N-(3-cyanophenyl)-2-isopropyl-5-methylcyclohexane-carboxamide.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. Ser. No.
11/437,294, filed May 19, 2006 which is a continuation-in-part of
International Application No. PCT/CH2004/000646 filed Oct. 28,
2004., under 35 USC .sctn.120 and .sctn.365(c), which claims the
benefit of the filing date of U.S. Provisional Application No.
60/523,977 filed Nov. 21, 2003.
[0002] This invention relates to cooling compounds.
[0003] Cooling compounds, that is, chemical compounds that impart a
cooling sensation to the skin or the mucous membranes of the body,
are well known to the art and are widely used in a variety of
products such as foodstuffs, tobacco products, beverages,
dentifrices, mouthwashes and toiletries.
[0004] One class of cooling compounds that have enjoyed substantial
success consists of N-substituted p-menthane carboxamides. Examples
of these compounds are described in, for example, British Patents
GB 1.351.761-2 and U.S. Pat. No. 4,150,052.
[0005] It has now been found that a particular selection of such
compounds exhibits a cooling effect that is both surprisingly
strong and long-lasting. There is therefore provided a compound of
the formula I
##STR00002##
in which m is 0 or 1, Y and Z are selected independently from the
group consisting of H, OH, C1-C4 straight or branched alklyl, or, a
C1-C4 straight or branched alkoxy, X is (CH.sub.2).sub.n--R, where
n is 0 or 1 and R is a group selected from halogens, OH, OMe,
NO.sub.2, CN, Ac, SO.sub.2NH.sub.2, CHO, CO.sub.2H and
C.sub.1-C.sub.4 alkyl carboxylates, with the provisos that:
[0006] (a) when Y and Z are H, X is not F, OH, MeO or NO.sub.2 in
the 4-position and is not OH in the 2 or 6-position,
[0007] (b) when Y or Z is H then X, Y and Z are such that [0008]
(i) the groups in the 3- and 4-positions are not both OMe, [0009]
(ii) the groups in the 4- and 5-positions are not both OMe, [0010]
(iii) the groups in 3- and 5-positions are not OMe if the group in
the 4-position is OH, and [0011] (iv) the groups in the 3- and
5-positions are not OH if the group in the 4-position is
methyl.
[0012] Particular subject cooling compounds include those in which
X is in the 4-position. The most preferred compounds are When X is
in the 4-position and Y and Z are H, OH, Me or OMe.
[0013] The cooling compounds of formula I have 3 chiral centres,
giving rise to 8 stereoisomers. All possible stereoisomers are
included in the scope of the present embodiments. The resolution of
stereoisomers is well within the skill of the art, but it can add
to the cost of these compounds, sometimes substantially. It may
therefore often be preferred to use the compounds as racemic
mixtures simply for economic reasons. However, if it is desired to
prepare individual stereoisomers, this may be achieved according to
methodology known in the art, e.g. preparative HPLC and GC on
chiral stationary phases, by stereoselective synthesis, or starting
from available chiral raw materials.
[0014] In a particular embodiment, the configuration of the
compound is (1R, 2S, 5R).
[0015] In particular embodiments of Formula I;
[0016] (A) In is 0 or 1; X is --(CH.sub.2).sub.n--R, where n is 0
or 1 and R is selected from the group consisting of --OR', --COOH,
--COOR'', --SO.sub.2NH.sub.2, --CHO, --COR''', and --CN, R' being
selected from H and C.sub.1-C.sub.3 straight- and branched-chain
alkyl R'' being selected from C.sub.1-C.sub.4 straight- and
branched-chain alkyl and R''' being selected from C.sub.1-C.sub.3
straight- and branched-chain alkyl; and Y is selected from the
group consisting of H, --COOH and --OR''', where R''' has the
significance previously referred to; and Z is H; with the provisos
that [0017] (i) when Y is H, X is not --OH, --CN, --OMe or --COOH
in the 4-position and not --OH in the 2-position; [0018] (ii) when
Y has a significance other than H, Y is in the 5-position When X is
in the 2-position and in the 6-position when X is in the
3-position; [0019] (iii) the groups in the 3- and 4-positions are
not both OMe, [0020] (iv) the groups in the 4- and 5-positions are
not both OMe, [0021] (v) the groups in 3- and 5-positions are not
OMe if the group in the 4-position is OH, and [0022] (vi) the
groups in the 3- and 5-positions are not OH if the group in the
4-position is methyl.
[0023] (B) m, X and Y are as in embodiment (A),A with the provisos
that [0024] (i) when Y is H and X is any of the abovementioned
significances, except --CN and --COOH, X is in the 4-position;
[0025] (ii) when Y is a moiety other than H, Y is in the 5-position
when X is in the 2-position and in the 6-position when X is in the
3-position.
[0026] (C) (a) m=0. [0027] (b) X is in either the 2- or the
4-position, and when in the 2-position is CN and when in the
4-position is selected from the group consisting of --COOH,
--COOCH.sub.3, --COOCH.sub.2CH.sub.3, --CN and --SO.sub.2NH.sub.2;
and [0028] (c) Y is selected from --CH.sub.3 in the 2-position and
--OCH.sub.3 in the 3-position.
[0029] Other particular embodiments are cooling compounds of the
following formulae set forth in Table A (the accompanying numbers
are the numbers of the relevant examples).
TABLE-US-00001 TABLE A ##STR00003## ##STR00004## ##STR00005##
##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023##
[0030] In other particular embodiments, the
2-isopropyl-5-methylcyclohexane moiety has the stereochemical
configuration (1R, 2S, 5R), and
[0031] (a) m=0.
[0032] (b) X is in either the 2- or the 4-position, and ashen in
the 2-position is CN and When in the 4-position is selected from
the group consisting of --COOH, --COOCH.sub.3,
--COOCH.sub.2CH.sub.3, --CN and --SO.sub.2NH.sub.2; and
[0033] (c) Y is selected from --CH.sub.3 in the 2-position and
--OCH.sub.3 in the 3-position.
[0034] The present cooling compounds may be prepared by reaction of
arylalkylamine derivative with an appropriate acid chloride or
carbonyl chloride. The carbonyl chloride may be prepared from
1-menthol ((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexanol).
[0035] They are distinguished from similar compounds of the prior
art by their surprisingly high cooling effect (up to 10 times
higher than that of similar known compounds) and by the longevity
of the cooling effect, which adds to their attractiveness in a
large variety of products.
[0036] For example, a small group of panelists was asked to taste
various solutions of cooling compounds and indicate which solutions
had a cooling intensity similar or slightly higher than that of a
solution of menthol at 2 ppm. In a second experiment, the same
panel was asked to taste the solutions at the chosen concentrations
and to record the cooling intensity at regular time intervals until
no cooling could be sensed in the mouth. Results are shown in table
1.
TABLE-US-00002 TABLE 1 experiment on cooling intensity and
longevity. Concen- Chemical tration Longevity 1-Menthol 2.0 ppm 35
minutes N-ethyl p-menthanecarboxamide (WS-3) 1.5 ppm 57 minutes
Formula 1, m = 0, Y = Z = H, X = 4-CN 0.5 ppm 90 minutes Formula 1,
m = 0, Y = Z = H, X = 4-CH.sub.2CN 0.2 ppm 93 minutes
[0037] From Table 1, it can be seen that the compounds of Formula I
are up to 10 times stronger and last up to 3 times longer than
menthol, the reference cooling compound. Compounds of Formula I are
also much stronger and last longer than WS-3, the best cooling
compound of the prior art.
[0038] The subject cooling compounds may be used in products that
are applied to the mouth or the skin to give a cooling sensation.
By "applying" is meant any form of bringing into contact, for
example, oral ingestion or, in the case of tobacco products,
inhalation. In the case of application to the skin, it may be, for
example, by including the compound in a cream or salve, or in a
sprayable composition. Therefore, also provided is a method of
providing a cooling effect to the mouth or skin by applying thereto
a product comprising a compound as hereinabove described. Specific
examples of products include, but are not limited to, the
following:
[0039] Consumable products, including, but not limited to all food
products, food additives, nutraceuticals, pharmaceuticals and any
product placed in the mouth including chewing gum, oral care
products, and oral hygiene products including but not limited to,
cereal products: rice products, tapioca products, sago products,
baker's products, biscuit products, pastry products, bread
products, confectionery products, dessert products, gums, cheering
gums, mouthwash, denial floss, flavored or flavor-coated straws,
flavor or flavor-coated food/beverage containers; chocolates, ices,
honey products, treacle products, yeast products, baking-powder,
salt and spice products, savory products, mustard products, vinegar
products, sauces (condiments), tobacco products, cigars,
cigarettes, processed foods, cooked fruits and vegetable products,
meat and meat products, jellies, jams, fruit sauces, egg products,
milk and dairy products, yoghurts; cheese products, butter and
butter substitute products, milk substitute products, soy products,
edible oils and fat products, medicaments, beverages, carbonated
beverages, alcoholic drinks such as beers, wines and spirits,
non-alcoholic drinks such as soft drinks, mineral and aerated
waters, fruit drinks, fruit juices, coffee, artificial coffee, tea,
cocoa, including forms requiring reconstitution including, without
limitation, beverage powder, milk based beverage powder, sugar-free
beverage powder, beverage syrup, beverage concentrate, instant
coffee, instant tea. instant cocoa, and coffee whitener food
extracts, plant extracts, meat extracts, condiments, gelatins,
pharmaceutical and non-pharmaceutical gums, tablets, lozenges,
drops, emulsions, elixirs, syrups and other preparations for making
beverages, and combinations thereof.
[0040] Oral care products, as hereinabove mentioned, include any
composition applied to the oral cavity for the purposes of
cleaning, freshening, healing, deodorising the cavity or any part
thereof, may include, but are not limited to, toothpastes, tooth
gels, tooth powders, tooth whitening products, mouthwashes,
lozenges, dental floss, toothpicks, anti-plaque and anti-gingivitis
compositions, throat lozenges, throat drops, inflammatory
compositions, compositions for treatment of nasal symptoms, cold
symptoms and upper gastrointestinal tract distress, compositions
for cold relief, for alleviating discomfort of hot flash: gargle
compositions.
[0041] Cosmetic products, such as aftershave lotions, baby
products, including lotions, oils, powders, creams and shampoos,
basecoats and undercoats, bath preparations- including capsules,
oils, tablets, salts, soaps and detergents, beard softeners,
blushers, body and hand preparations. bubble baits, cleaning
products, colognes and toilet waters, cuticle softeners,
dentifrices. deodorants, depilatories, douches, eye lotions, eye
makeup preparations including eye makeup removers, else shadows,
eyebrow pencils and eyeliners, face and neck preparations, face
powders, feminine hygiene deodorants, foot powders and sprays,
foundations, fragrance preparations, hair and scalp preparations
including bleaches, colour spray s and other colouring preparations
such as dyes and colours, hair lighteners with colour, hair
conditioners, hair preparations, hair rinses, hair shampoos, hair
sprays, hair straighteners, hair tints, hair tonics. hair wave
sets, indoor tanning preparations, leg and body paints, lipsticks,
makeup bases, makeup preparations including fixatives, manicuring
preparations, mascara, men's talcum, moisturising preparations,
nail creams and lotions, nail extenders, nail polish and enamel
removers, nail polish and enamels, night skin care preparations,
paste masks, perfumes, permanent waves, personal cleanliness
products, powders, preshave lotions, rouges, sachets, shampoos,
shaving creams shaving preparations miscellaneous, shaving soap,
skin care preparations, including fresheners, suntan preparations
including gels, creams and liquids.
[0042] The subject cooling compounds may be used alone or in
combination with other cooling compounds known in the art, e.g.,
menthol, menthone, isopulegol, N-ethyl p-menthanecarboxamide
(WS-3), N,2,3-trimethyl-2-isopropylbutanamide (WS-23), menthyl
lactate (Frescolat.TM. ML), menthone glycerine acetal
(Frescolat.TM. MGA), mono-menthyl succinate (Physcool.TM.),
mono-menthyl glutarate, O-menthyl glycerine (CoolAct.TM. 10),
menthyl-N,N-dimethylsuccinamate and 2-sec-butylcyclohexanone
(Freskomenthe.TM.).
[0043] The subject cooling compounds are nov further described by,
means of the following non-limiting examples, which describe
particular embodiments.
[0044] The starting compound p-menthane-3-carbonyl chloride as used
for the preparation of the compounds in Example 1-31 was prepared
from 1-menthol.
EXAMPLE 1
Preparation of N-(4-cyanomethylphenyl) p-menthanecarboxamide
[0045] To a flask were added 6.6 g (50 mmol) of 4-aminobenzyl
cyanide, 4.04 mL of pyridine and 100 mL MtBE. To this mixture, 10 b
of p-menthane-3-carbonxyl chloride were added dropwise over 5
minutes. The reaction mixture was stirred for 24 h. To the reaction
mixture, 50 mL of water were added. The mixture as separated. The
organic layer was washed with 50 mL of water and 50 mL of brine.
The organic laver was dried over MgSO.sub.4. The solvent as
evaporated in vacuo to afford the crude product, which w as
recrystallized from hexanes to afford 10.1 g of the desired product
with the following spectroscopic properties:
[0046] MS: 29.9 ([M+1]), 298 ([M.sup.30]) ,132,83
[0047] .sup.1H NMR (300 MHz; CDCl.sub.3) .delta.: 7.58 (d 2H), 7.49
(s, 1H), 7.27 (d, 2H): 3.73 (s, 2H), 2.2 (t, 1H), 1.96-1.57 (m,
5H), 1.48-1.21 (m, 2H), 1.172- 0.99 (m, 2H), 0.94 (d, 3H), 0.93 (d,
3H), 0.85 (d, 3H)
[0048] .sup.13C NMR (75 MHz. CDCl.sub.3).delta.: 174.4, 137.8,
128.3, 125.1, 120.3, 118.2, 50.5, 44.3, 39.25, 34.3, 32.1, 28.7,
23.8, 22.9, 22.1, 21.2, 16.1
EXAMPLE 2
Preparation of N-(4-sulfamoylphenyl) p-menthanecarboxamide
[0049] A preparation similar to that described in example 1 gives
the desired product with the following spectroscopic
properties:
[0050] MS: 339([M+1]), 338([M.sup.+]), 172, 83
[0051] .sup.1H NMR (300 MHz; DMSO) .delta.: 10.21 (s, 1H), 7.76 (d,
1H) 7.73 (d, 2H), 7.23 (s, 2H), 2.26-2.42 (m, 1H), 1.45-1.85 (m,
5H), 1.29-1.44 (m, 2H), 0.89 (d, 3H), 0.86 (d,3H), 0.78 (d, 3H)
[0052] .sup.13C NMR (75 MHz; DMSO) .delta.: 174.6, 142.3, 138.3,
126.7, 118.8, 48.9, 43:7, 34.3, 31.9, 28.6, 23.7, 22.35, 21.3,
16.25
EXAMPLE 3
Preparation of N-(4-cyanophenyl) p-menthanecarboxamide:
[0053] A preparation similar to that described in example 1 gives
the desired product with the following spectroscopic
properties:
[0054] MS: 285([M+1]), 284 ([M.sup.+]), 139.83
[0055] .sup.1H NMR (300 MHz; CDCl.sub.3) .delta.: 7.69 (d, 2H), 7.6
(d, 2H), 7.5 (s, 1H), 1.85-1.97 (m, 1H), 1.69-1.84 (m, 3H),
1.55-1.69 (m, 2H), 1.21-1.47 (m, 2H), 0.979-1.16 (m, 2H), 0.95 (d,
3H), 0.93 (d, 3H), 0.82 (d, 3H)
[0056] .sup.13C NMR (300 MHz; CDCl.sub.3) .delta.: 174.6, 133.1,
119.4, 118.7, 100.35, 50.7, 44.4, 39.25, 34.2, 32.1, 2.8, 23.7,
22.0, 21.2,: 16.1, 14.0
EXAMPLE 4
Preparation of N-(4-acetylphenyl) p-menthanecarboxamide
[0057] A preparation similar to that described in example 1 gives
the desired product with the following spectroscopic
properties:
[0058] MS: 302([M+1]), 301([M.sup.+]), 135, 83
[0059] .sup.1H NMR (300 MHz; CDCl.sub.3) .delta.: 7.93 (d, 2H) 7.66
(d, 2H), 7.63 (s, 1H ), 2.57 (s, 3H), 2.09-2.31 (m, 1H), 1.84-1.98
(m, 1H), 1.68-1.85 (m, 5H), 1.56-1.68 (m, 2H), 1.17-1.48 (m, 2H),),
0.93 (d, 3H), 0.91 (d, 3H), 0.83 (d, 3H)
[0060] .sup.13C NMR (75 MHz; CDCl.sub.3) .delta.: 197.1, 174.9,
142.7, 129.9, 119.2, 51.2, 44.9, 39.8, 34.8, 32.6, 29.2, 26.6,
24.3, 22.4, 21.5, 16.6
EXAMPLE 5
Preparation of N-(4-hydroxymethylphenyl) p-menthanecarboxamide
[0061] A preparation similar to that described in example 1 gives
the desired product with the following spectroscopic
properties:
[0062] MS: 290 (M+1), 289 (M.sup.+), 123, 83
[0063] .sup.1HNMR (300 MHz, DMSO) .delta.: 9.9 (s, 1H) 7.54 (d,
2H), 7.21 (d, 2H), 4.2 (s, 2H), 2.36-2.1 (m, 1H), 1.8-1.59 (m, 6H),
1.57-1.44 (m, 1H), 1.21-0.9 (m, 4H), 0.87 (dd, 3H), 0.85 (dd, 3H)
0.79 (d, 2H)
[0064] .sup.13C NMR (75 MHz; DMSO) .delta.: 173.7, 137.7, 137.1,
126.7, 118.9, 62.6, 48.6, 43.6. 34.2, 31.7, 28.3, 23.6, 22.2, 21.1,
16.1
EXAMPLE 6
Preparation of N-(3-hydroxy-4-methoxyphenyl)
p-menthanecarboxamide
[0065] A preparation similar to thai described in example I gives
the desired product with the following spectroscopic
properties:
[0066] MS: 306([M+1]). 305([M.sup.+]), 139, 83
[0067] .sup.1H NMR (300 MHz; CDCl.sub.3) .delta.: 7.14 (s, 1H),
7.08 (d, 1H), 6.78 (d, 1H), 5.7 (s, 1H), 3.8 (s, 3H), 2.02-2.21 (m,
2H), 1.53-1.94 (m, 5H), 1.17-1.48 (m, 2H), 0.97-1.17 (m, 2H), 0.92
(dd, 3H), 0.91 (dd, 3H), 0.82 (d, 3H)
[0068] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.: 173.9, 145.6,
143.3, 131.7. 111.65, 110.8, 107.4, 56.1. 50.5, 44.4, 39.2 32.15.
34.4. 28.6 23.8, 22.1, 21.2 16.1
EXAMPLES 7-31
[0069] The following compounds were made by methods analogous to
those previously described.
TABLE-US-00003 TABLE B Example No. Compound and properties 7
(1R,2S,5R)-N-(4-isopropoxybenzyl)-2-isopropyl-5-
methylcyclohexanecarboxamide .sup.1H NMR (DMSO) .delta.: 8.36-8.15
(t, 1H), 7.20-7.02 (d, 2H), 6.91-6.76 (d, 2H), 4.70-4.42 (m, 1H),
4.28-4.05 (d, 2H), 2.19-2.07 (t, 1H), 1.79-1.30 (m, 6H), 1.28-1.20
(d, 6H), 1.15-1.05 (m, 1H), 0.92-0.70 (m, 11H). LC-MS: 332.2
(M.sup.+), 354.3 (M.sup.+22). 8
(1R,2S,5R)-2-isopropyl-5-methyl-N-(4-propionylphenyl)-
cyclohexanecarboxamide .sup.1H NMR (CDCl.sub.3) .delta.: 8.01-7.87
(d, 2H), 7.70-7.57 (d, 2H), 3.05-2.88 (q, 2H), 2.25-2.10 (t, 1H),
1.99-1.87 (d, 1H), 1.85-1.58 (m, 4H), 1.52-1.15 (m, 5H), 1.12-0.96
(m, 2H), 0.94-0.89 (d, 6H), 0.87-0.78 (d, 3H). LC-MS: 338.0
(M.sup.+23). 9 methyl
4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)-2-methoxybenzoate .sup.1H NMR (CDCl.sub.3) .delta.:
7.89-7.67 (m, 2H), 6.83-6.68 (d, 1H), 4.00- 3.91 (s, 3H), 3.90-3.81
(s, 3H), 2.25-2.03 (t, 1H), 1.97-1.50 (m, 7H), 1.47-1.21 (m, 2H),
1.15-0.89 (m, 8H), 0.87-0.78 (d, 3H). LC-MS: 346.0 (M.sup.-) 10
butyl 4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)benzoate .sup.1H NMR (DMSO) .delta.: 10.32-10.15 (s,
1H), 7.94-7.82 (d, 2H), 7.80- 7.69 (d, 2H), 4.31-4.16 (t, 2H),
2.42-2.27 (t, 1H), 1.87-1.30 (m, 10H), 1.21-1.09 (m, 1H), 0.99-0.72
(m, 14H). LC-MS: 358.2 (M.sup.-). 11 ethyl
3-((1R,2R,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)-4-propoxybenzoate .sup.1H NMR (CDCl.sub.3) .delta.:
9.01 (s, 1H), 7.87-7.70 (m, 2H), 6.93-6.82 (d, 1H), 4.42-4.26 (q,
2H), 4.12-3.99 (t, 2H), 2.27-2.11 (td, 1H), 1.98- 1.67 (m, 6H),
1.65-1.59 (m, 1H), 1.45-1.27 (t, 5H), 1.12-0.97 (t, 5H), 0.97-0.89
(m, 6H), 0.85-0.79 (d, 3H). LC-MS: 412.3 (M.sup.+23). 12 ethyl
2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)-4-methoxybenzoate .sup.1H NMR (CDCl.sub.3) .delta.:
11.40 (s, 1H), 8.50 (s, 1H), 8.02-7.88 (d, 1H), 6.65-6.52 (d, 1H),
4.45-4.28 (q, 2H), 3.87 (s, 3H), 2.36-2.21 (td, 1H), 1.98-1.60 (m,
5H), 1.47-1.22 (m, 5H), 1.12-0.97 (m, 2H), 0.96- 0.89 (d, 6H),
0.88-0.80 (d, 3H). LC-MS: 384.3 (M.sup.+23). 13 methyl
4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)-3-methylbenzoate .sup.1H NMR (CDCl.sub.3) .delta.:
8.23-8.12 (d, 1H), 7.95-7.82 (m, 2H), 7.11- 6.99 (s, 1H), 3.91
(s,3H), 2.31 (s, 3H), 2.28-2.15 (t, 1H), 1.99-1.89 (d, 1H),
1.88-1.68 (m, 3H), 1.66-1.60 (m, 1H), 1.48-1.22 (m, 2H), 1.18-0.97
(m, 2H), 0.96-0.90 (d, 6H), 0.88-0.81 (d, 3H). LC-MS: 332.1
(M.sup.+), 354.1. (M.sup.+23). MP: 147-149.degree. C. 14 tert-butyl
4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane- carboxamido)benzoate
MS: 359, 303, 386, 260, 248, 235, 221, 207, 193, 179, 167, 137,
136, 120, 97, 83, 69, 55, 41, 32 15 methyl
4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane- carboxamido)benzoate
MS: 317, 302, 286, 260, 248, 221, 206, 193, 178, 167, 151, 139,
135, 120, 97, 83, 69, 57, 55, 41 Mp: 136-138.degree. C. 16 ethyl
4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane- carboxamido)benzoate
.sup.1H NMR (CDCl.sub.3) .delta.: 8.05-7.95 (d, 2H), 7.67-7.59 (d,
2H), 7.46-7.40 (s, 1H), 4.44-4.29 (t, 2H), 2.25-2.1 (td, 1H),
1.97-1.86 (d, 1H), 1.85- 1.58 (m, 4H), 1.45-1.35 (m, 4H), 1.35-1.22
(t, 2H), 1.11-0.98 (m, 1H), 0.97-0.88 (q, 6H), 0.87-0.77 (d, 3H).
.sup.13C NMR (CDCl.sub.3) .delta.: 224, 182.2, 174.4, 141.95,
130.6, 118.6, 60.7, 50.8, 44.4, 39.3, 34.3, 32.1, 28.7, 23.8, 22.1,
21.2, 16.1, 14.2. GC-MS: 331 (M), 286, 220, 207, 165, 139, 120, 97,
83, 55, 41. MP: 167-169 C. 17
2-[(2-Isopropyl-5-methyl-cyclolhexanecarbonyl)-amino]-benzoic acid
methyl ester .sup.1H NMR (CDCl.sub.3) .delta.: 11.21-11.05 (s, 1H),
8.88-8.72 (d, 1H), 8.11- 7.97 (d, 1H), 7.65-7.47 (t, 1H), 7.15-6.99
(t, 1H), 3.99-3.88 (s, 3H), 2.37-2.20 (td, 1H), 2.03-1.88 (d, 1H),
1.87-1.57 (m, 4H), 1.54-1.22 (m, 3H), 1.20-0.99 (m, 2H), 0.98-0.88
(dd, 6H), 0.88-0.79 (d, 3H). .sup.13C NMR (CDCl.sub.3) .delta.:
175.1, 168.6, 141.6, 134.5, 130.6, 122.06, 120.2, 114.6, 100.3,
52.1, 51.6, 44.5, 39.3, 34.4, 32.1, 28.7, 23.8, 22.1, 21.2, 15.9.
GC-MS: 317 (M), 286, 221, 193, 174, 151, 146, 119, 83, 55, 41. 18
2-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane- carboxamido)benzoic
acid .sup.1H NMR (CDCl.sub.3) .delta.: 11.1-10.97 (s, 1H),
8.88-8.76 (d, 1H), 8.23-8.1 (d, 1H), 7.7-7.52 (t, 1H), 7.21-7.06
(t, 1H), 2.42-2.22 (td, 1H), 2.06- 1.9 (d, 1H), 1.9-1.55 (m, 5H),
1.54-1.22 (m, 4H), 1.21-1.01 (m, 2H), 1.0-0.91 (q, 6H), 0.89-0.79
(d, 3H). .sup.13C NMR (CDCl.sub.3) .delta.: 175.6, 172.2, 141.9,
135.5, 131.6, 122.5, 120.5, 113.8, 51.7, 44.6, 39.3, 34.4, 32.1,
31.4, 28.7, 23.8, 22.5, 22.1, 21.2, 15.9. GC-MS: 303 (M), 260, 221,
207, 179, 146, 137, 119, 95, 83, 55, 41. 19
(1R,2S,5R)-N-(4-formylphenyl)-2-isopropyl-5-methylcyclo-
hexanecarboxamide GC-MS: 287 (M), 244, 191, 176, 167, 139, 121, 83,
69, 55, 41. 20 2-Isopropyl-5-methyl-cyclohexanecarboxylic acid
(2,4- dimethoxy-phenyl)-amide .sup.1H NMR (CDCl.sub.3) .delta.:
8.32-8.23 (d, 1H), 7.59-7.49 (s, 1H), 6.52-6.43 (2 s, 2H),
3.89-3.83 (s, 3H), 3.81-3.75 (s, 3H), 2.23-2.1 (td, 1H), 1.96-1.56
(m, 5H), 1.49-1.24 (m, 2H), 1.17-0.97 (m, 2H), 0.96-0.88 (d, 6H),
0.87-0.77 (d, 3H). .sup.13C NMR (CDCl.sub.3) .delta.: 173.6. 156.0,
148.9, 121.2, 120.5. 103.5, 100.3, 98.4, 55.5, 55.4, 50.7, 44.5,
39.3, 34.4, 32.1, 28.5, 23.8, 22.1, 21.2, 15.9. GC-MS: 319 (M),
248, 223, 195, 179, 153, 138, 110, 95, 83, 55, 41. 21
2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (2-hydroxy-4-
methyl-phenyl)-amide .sup.1H NMR (CDCl.sub.3) .delta.: 8.42-8.32
(s, 1H), 7.96-7.88 (s, 1H), 7.25-7.18 (m, 1H), 7.04-6.95 (d, 1H),
6.46-6.36 (d, 1H), 2.25-2.19 (s, 3H), 2.18-2.08 (m, 1H), 1.96-1.58
(m, 6H), 1.45-1.25 (m, 2H), 1.17-0.95 (m, 2H), 0.95-0.91 (d, 3H),
0.90-0.86 (s, 3H), 0.85-0.77 (d, 3H). .sup.13C NMR (CDCl.sub.3)
.delta.: 175.1, 155.5, 136.1, 130.2, 120.8, 109.8, 107.3, 50.9,
44.2, 39.0, 34.3, 32.2, 28.6, 23.9, 22.1, 21.0, 16.1, 15.4. GC-MS:
289 (M), 246, 178, 165, 123, 83, 55, 41. 22 ethyl
2-((1R,2S,5R)-2-isopropyl-5- methylcyclohexanecarboxamido)benzoate
.sup.1H NMR (CDCl.sub.3) .delta.: 11.3-11.02 (s, 1H), 8.87-8.71 (d,
1H), 8.11- 7.96 (d, 1H), 7.61-7.43 (t, 1H), 7.12-6.97 (t, 1H),
4.50-4.29 (q, 2H), 2.38-2.17 (td, 1H), 2.01-1.87 (d, 1H), 1.86-1.57
(m, 4H), 1.52-1.40 (t, 3H), 1.38-1.21 (m, 2H), 1.15-0.98 (m, 2H),
0.96-0.88 (dd, 6H), 0.85-0.76 (d, 3H). .sup.13C NMR (CDCl.sub.3)
.delta.: 175.2, 168.3, 141.8, 134.5, 130.7, 122.1, 120.4, 115.1,
61.3, 51.8, 44.7, 39.5, 34.6, 32.3, 28.9, 24.0, 22.3, 21.3, 16.1,
14.2. GC-MS: 331 (M), 286, 220, 207, 174, 165, 146, 119, 95, 83,
69, 55, 41. 23 4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)benzoic acid MP: 262-264 C. .sup.1H NMR
(CDCl.sub.3/MeOD) .delta.: 8.0 (d, 2H), 7.7 (d, 2H), 2.3 (dt, 1H),
1.9-1.6 (m, 5H), 1.4-1.2 (m, 2H), 1.15-1.0 (m, 2H), 0.94, d, 6H),
0.85 (d, 3H) 24 4-(((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)methyl)benzoic acid MP: 220-225 C. 25
(1R,2S,5R)-N-(4-cyanobenzyl)-2-isopropyl-5-
methylcyclohexanecarboxamide MP: 148-154 C. .sup.1H NMR
(CDCl.sub.3/MeOD) .delta.: 7.62 (d, 2H), 7.37 (d, 2H), 5.89 (b,
1H), 4.5 (d, 2H), 2.07 (dt, 1H), 1.85-1.65 (m, 4H), 1.6-1.5 (m,
1H), 1.4- 1.2 (m, 2H), 1.15-0.95 (m, 2H), 0.9 (d, 6H), 0.78 (d, 3H)
26 2-hydroxy-5-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)benzoic acid 27
(1R,2S,5R)-2-isopropyl-5-methyl-N-(4-sulfamoylbenzyl)-
cyclohexanecarboxamide MP: 160-170 .sup.1H NMR (CDCl.sub.3/MeOD)
.delta.: 7.82 (t, 2H), 7.32 (m, 3H), 4.44 (d, 2H), 2.2-2.0 (m, 1H),
1.9-1.6 (m, 5H), 1.6-1.45 (m, 1H), 1.4-1.1 (m, 2H) 1.1-1.0 (m, 2H),
0.94-0.87 (m, 6H), 0.83-0.75 (m, 3H). 28
4-(((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanecarboxamido)-
methyl)benzoic acid 29 ethyl
2-(4-((1R,2S,5R)-2-isopropyl-5-methylcyclohexane-
carboxamido)phenyl)acetate 30
(1R,2S,5R)-N-(2-cyanophenyl)-2-isopropyl-5-
methylcyclohexane-carboxamide .sup.1H NMR (CDCl.sub.3) .delta.:
8.46 (d, 1H), 7.62-7.56 (m, 3H), 7.14 (t, 1H), 2.30-2.23 (td, 1H),
1.98-1.93 (d, 1H), 1.82-1.62 (m, 4H), 1.36-1.28 (m, 2H), 1.12-1.02
(m, 2H), 0.99-0.93 (dd, 6H), 0.87-0.85 (d, 3H). .sup.13C NMR
(CDCl.sub.3) .delta.: 174.58, 140.59, 134.15, 132.07, 123.94,
132.07, 123.94, 121.29, 116.32, 101.81, 51.0, 44.84, 39.44, 34.43
32.23, 28.99, 23.96, 22.21, 21.29, 16.23 31
(2S,5R)-N-(3-cyanophenyl)-2-isopropyl-5-methylcyclohexane-
carboxamide .sup.1H NMR (CDCl.sub.3) .delta.: 8.15 (s, 1H), 7.98
(s, 1H), 7.80-7.75 (td, 1H), 7.43-7.33 (m, 2H), 2.30-2.23 (td, 1H),
1.92-1.85 (d, 1H), 1.82-1.55 (m, 4H), 1.40-1.20 (m, 2H), 1.10-0.95
(m, 2H), 0.95-0.87 (dd, 6H), 0.87-0.83 (d, 3H). .sup.13C NMR
(CDCl.sub.3) .delta.: 175.25, 139.10, 129.80, 127.45, 124.27,
123.16, 118.59, 112.69, 50.49, 44.50, 39.42, 34.44, 32.26, 28.98,
23.95, 22.23, 21.34, 16.31
EXAMPLE 32
Testing of Compounds
[0070] A small group of panelists were asked to taste various
aqueous solutions of compounds. The compounds were first dissolved
in ethanol at 1% by weight and then dosed into water. The panelists
were asked to indicate which solutions had a cooling intensity
similar to or slightly higher than that of a solution of menthol at
2 ppm. The results are shown in Table 2.
TABLE-US-00004 TABLE 2 Concen- Compound/ tration Example No. [ppm]
Description 7 0.01 slight delay in onset, builds to similar or
slightly cooler than menthol, teeth and gums 9 0.005 Similar to
menthol, refreshing, slightly bitter long lasting 15 2 slightly
cooling, flat cooling 16 2 Cooling similar to menthol 19 2 cooling
builds and lingers 23 2 slightly burning then cooling 24 2 little
cooling, slightly refreshing 25 2 good icy cooling, slightly
astringent 27 2 Similar to reference, builds up 28 2 strong cooling
up front, peppery heat 29 2 icy, crisp cool on tongue 30 2 clean,
slightly stronger than menthol 31 1 weak cooling, tingling, numbing
on tongue, 32 2 mouthcoating, more cooling than menthol
EXAMPLE 34
Application in Mouthwash
TABLE-US-00005 [0071] Alcohol 95% 177 mL Sorbitol 70% 250 g
Compound of example 1 as 50 mL a 1% solution in alcohol Peppermint
oil, Terpeneless 0.300 g Methyl salicylate 0.640 g Eucalyptol 0.922
g Thymol 0.639 g Benzoic acid 1.500 g Pluronic .TM. F127 5.000 g
Sodium Saccharin 0.600 g Sodium Citrate 0.300 g Citric Acid 0.100 g
Water q.s. 1 liter
[0072] The ingredients are mixed, 30 mL of obtained solution is put
in the mouth, swished around. gargled and spit out. An intense
cooling is felt in every area of the mouth as well as the lips. The
cooling perception lasts for several hours.
EXAMPLE 35
Application in Toothpaste
TABLE-US-00006 [0073] Opaque toothgel 97.000 g Compound of example
2 2.500 g as a 2% solution in PG Peppermint oil, Terpeneless 0.500
g
[0074] The materials are mixed in the toothgel, and a panelist's
teeth are brushed using this toothgel. The mouth is rinsed with
water and the water spit out. An intense cooling sensation is felt
by the panelist in all areas of the mouth. The cooling perception
lasts for several hours.
[0075] It will be understood that the embodiments described herein
are merely exemplary, and that one skilled in the art may make
variations and modifications without departing from the spirit and
scope of the invention. All such variations and modifications are
intended to be included within the scope of the invention as
described hereinabove. Further, all embodiments disclosed are not
necessarily in the alternative, as various embodiments of the
invention may be combined to provide the desired result.
* * * * *